Marijuana cannabinoids have been shown to modulate various immune functions through mechanisms involving cannabinoid 1 (CB1) and cannabinoid 1 (CB2) receptors. Several studies have also concluded that other receptors are in involved (Begg et al., (2005) Pharmacol. Ther. 106: 133-145) because immune modulation by THC persists in CB1- and CB2-deficient mice (Walter & Stella (2004) Br. J. Pharmacol. 141: 775-785; Lu et al., (2006) Eur. J. Pharmacol. 532: 170-177; Springs et al., (2008) J. Leukoc. Biol. 84: 1574-1584). A third cannabinoid receptor. GPR55, has been reported and may account for some of the effects observed in the relative absence of CB1 and CB2, GPR55 is stimulated by THC as well as other cannabinoid ligands (Ryberg et al., (2007) Br. J. Pharmacol. 152: 1092-1101) with one of these ligands, lysophosphatidylinositol (LPI), speculated to be the natural endogenous ligand for this receptor (Oka et al., (2009) J. Biochem. 145: 13-20).
Among the various immune mechanisms modulated by cannabinoids, T helper (Th) cell biasing has been reported with a suppression of Th1 and enhancement of Th2 immunity (Klein T W (2005) Nat. Rev. Immunol. 5; 400-411). This biasing effect of Th cells has also been observed with other neuroimmune agents such as morphine (Roy et al., (2001) Surgery 130: 304-309) and could partially explain the decrease in neuroinflammatory symptoms associated with Th1 activity (Maresz et al., (2007) Nat. Med, 13:492-497) or the increase in serum IgE levels (Th2 activity) observed in marijuana smokers (Rachelefsky et al., (1976) J. Allergy Clin. Immunol. 58: 483-490). In the first report of cannabinoid-induced Th biasing, a suppression of cell-mediated immunity and splenocyte IFN-γ production was accompanied by increasing serum levels of IgG1 antibodies and splenocyte IL-4 (Newton et al., (1994) Infect. Immun. 62: 4015-4020). Because the different subclasses of antibodies are regulated by Th cytokines with IL-4 increasing the synthesis of IgG1 and IgE (Roper et al., (1990) J. Immunol. 145: 2644-2651), these results suggested that THC might increase the production of the allergic antibody, IgE, in addition to IgG1.
Although it has been shown that CB2 receptors are expressed in peripheral tissues, including, but not limited to tonsils, thymus and spleen, and identified in cells of the central nervous system, it has also been shown that the CB2 receptor is expressed in inflammatory cells and immune competent cells (Howlett et al., (2002) Pharmacol. Rev. 54: 161-202; Bouaboula et al., (1999) J. Biol. Chem. 274: 20397-20405; Pertwee, R. G. (2006) Int. J. Obes. 30 (Suppl 1): S13-S18; Pertwee, R. G. (2006) Br. J. Pharmacol. 147 (Suppl 1): S163-S171; Jbilo et al., (1999) FEBS Lett. 448: 273-277; Kishimoto et al., (2004) J. Biochem. 135: 517-524).
Studies examining the effect of synthetic cannabinoid agonist JWH-015 on CB2 receptors revealed that changes in cAMP levels resulted in the phosphorylation of leukocyte receptor tyrosine kinase at Tyr-505. Through this mechanism, T cell receptor signaling was inhibited. These results further demonstrated the immunosuppressive properties of CB2 receptor agonists. Thus, CB2 agonists have been considered as possibly useful for treatment of inflammation and pain.